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This study developed a novel liposomal system combining CF and CA for the first time, formulated with either Lipoid S 75 or Phospholipon\u00ae 90 G and cholesterol (80:20 ratio), aiming to enhance skin penetration of CF and CA by encapsulating them into liposomes dermal application. Formulations with 1% CF and either 0.13% or 0.07% CA were developed and tested for skin permeation utilizing Franz diffusion cells with human cadaver skin. Receptor compartment samples were collected at 2, 4, 8, 12, and 24\u00a0h and the amount of CF penetrated (\u00b5g\/cm\n                    <jats:sup>2<\/jats:sup>\n                    ) was quantified using a validated HPLC method. The skin distribution in dermal and epidermal layers of both compounds were also assessed. Results showed that formulation F9 (1% CF, 0.13% CA) significantly improved skin penetration, doubling CF levels in the dermis and increasing CA levels by 5.5-fold in the dermis and 35-fold in the epidermis, despite lower CF permeability compared to the control. F9 also demonstrated high encapsulation efficiency and confirmed safety in cytotoxicity studies. These findings suggest that liposomal formulations of combining CF and CA are promising for topical applications and merit further clinical investigation.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1208\/s12249-025-03310-5","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T17:27:09Z","timestamp":1769102829000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Skin Penetration of Caffeine and Cafestol using Liposomes: Exploring the Benefits of a Combined Delivery System"],"prefix":"10.1208","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8545-9811","authenticated-orcid":false,"given":"Nubul","family":"Albayati","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3918-8994","authenticated-orcid":false,"given":"Amitkumar","family":"Virani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4303-1909","authenticated-orcid":false,"given":"Sesha Rajeswari","family":"Talluri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3858-158X","authenticated-orcid":false,"given":"Bozena","family":"Michniak-Kohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"3310_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/nu11020416","author":"MC Cornelis","year":"2019","unstructured":"Cornelis MC. 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